While normal cells possess mechanisms that inhibit proliferation when conditions are inappropriate, tumor cells circumvent these mechanisms and continue proliferating. These regulatory mechanisms are triggered by diverse stimuli such as cell-cell contact, when cells reach a critical number and density. This contact- inhibition often becomes dysregulated during tumorigenesis and our long-term goals are to identify and characterize the mechanisms of how cell:cell contact triggers anti-proliferative/growth control signals. A central player in the regulation of these signals is Merlin, the protein product of the NF2 (neurofibromatosis type 2) tumor suppressor gene. Recent studies have indicated the NF2 allele is functionally inactivated in a broad range of tumors. Merlin is localized to regions of cel-cell contacts and a major manifestation of Merlin's loss of function is the development of tumors in vivo and loss of contact inhibition of cell proliferation. Merlin has been shown to function a a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hpo/Yap pathway. While these pathways play critical roles in regulation of cell proliferation, organ size control and tissue repair, it is still not clear which of these pathways mediates Merlin's tumor suppressive function/s. We recently identified the Angiomotins, members of the Motin protein family, as Merlin-interacting proteins that localize to tight and adherens junctions. Importantly, we determined that Merlin's ability to regulate mitogenic signaling is mediated through the Angiomotins and that the Angiomotins are required for tumorigenesis in an animal model of NF2. Our working hypotheses are that Merlin functions as a tumor suppressor by regulating signaling pathways that control cellular proliferation through interaction with the Angiomotins and that targeting the Angiomotins will result in inhibition of tumorigenesis. We will test these hypotheses employing cell-based and animal models of NF2 to identify the mechanisms underlying Merlin and Angiomotin-dependent regulation of cell proliferation, establish the roles of the Hpo/Yap pathway and Angiomotin in NF2 and determine whether Angiomotins can drive tumorigenesis in vivo. Given the involvement of NF2 mutations in a broad spectrum of cancers, these studies will have broad impact and 1) elucidate the molecular mechanisms underlying regulation of cellular proliferation by cell:cell contact, 2) determine the functions of Merlin relevant to tumor suppression, 3) establish a role for the Hpo/YAP pathway and 4) validate the Angiomotins as novel targets for development of therapeutic interventions.